The objective of this study was to explore the association of gender to use of prayer as a self-care strategy for managing the HIV-related symptoms of fatigue, nausea, depression, and anxiety among African American men and women who are HIV-seropositive. To accomplish this, data were determined using convenience sampling from a sample of 448 African American men and women from the United States who were participants in a national study on self-care symptom management of HIV/AIDS. Chi-square analyses were used to examine the potential relationships between gender and the use of prayer for managing the four symptoms. The mean age of the sample was 42.69 +/- 7.93 years (range, 20-66). Results showed the following gender differences in the use of prayer as a self-care strategy: fatigue-men 46% (n = 62), women 54% (n = 74); nausea-men 52% (n = 33), women 48% (n = 30); depression-men 55% (n = 90), women 45% (n = 73); and anxiety-men 77% (n = 83), women 87% (n = 73). Chi-square analyses determined that significant differences exist between African American men and women in the frequency of the use of prayer for managing HIV-related fatigue (chi(2) = 14.81, 1 df, p = .000), nausea (chi(2) = 4.10, 1 df, p =.043), and depression (chi(2) = 5.21, 1 df, p = .022). There was no gender difference in the use of prayer to manage anxiety. Prayer was reported as a self-care strategy by over 50% of the respondents for three of the four symptoms and was rated highly efficacious. The authors conclude that the African American men and women differed in their selection of prayer as a self-care strategy for managing HIV-related depression, fatigue, and nausea. A higher proportion of women than men used prayer to manage fatigue, and more men than women reported using prayer to manage nausea and depression.